Protein Kinases are divided into two families (1) tyrosine kinase family and (2) serine and threonine kinase family depending on their phosphorylation site (tyrosine, or serine and threonine. Protein kinse activity controls a wide variety of cell life such as growth, differentiation and proliferation. Some of the examples for tyrosine kinase are ALK4, Azl, Brk, EphB4, Fer, Fgr, JAK family (JAK1 and JAK2), Ret, TrkA, Tec family BTK, IKK, ITK and examples for serine and threonine kinase are Ark5, Msk1, Nek2, Pim (Pim1 and Pim2), PLK, RockI and II, SGK1,2 3, MEK, Erk, Chk, Aurrora and C-met kinases.
C-Jun-N-terminal kinases (i.e., JNKs), which belong to the mitogen activated protein kinase family, are triggered in response to cytokines, mitogens, osmotic stress and ultraviolet readiation. JNKs are divided into three (JNK1, JNK2 and JNK3) major isoforms depending on their gene sequence. Further, these JNKs are divided into 10 splicing isoforms in cells (Gupta, S., T. Barret, A. J., Whitmarsh, J. Cavanagh, H. K. Sluss, B. Derijard, and R. J. Davis 1996, EMBO J. 15, 2760-2770). JNK1 and JNK2 are ubiquitously expressed (Mohit, A. A., Martin, J. H., Miller, C. A Neuron 14, 67-70, 1995), where as JNK3 is expressed in brain and to a lesser extent in the heart and testes.
JNKs are activated by dual phosphorylation of Thr 183 and Tyr 185 by MKK4 and MKK7 kinases (Lin A., Minden A., Martinetto H., Claret F.-Z., Lange-Carter C., Mercurio F., Johnson G. L., and Karin M. Science 268: 286-289, 1995). MKK4 preferentially phosphorylates JNK on tyrosine whereas MKK7 phosphorylates JNK on threonine. Activated c-Jun-N-terminal kinase in turn activates by phosphorylating various transcription factors such as c-Jun, AP1, ATF2, IRS1, NFAT4 and Bcl-2, etc. (Karin M and Hunter T. Curr. Biol. 5,747-757, 1995 and Shaulian, E., and Karin, M., Nat. Cell Biol. 4, E131-136, 2002). Either JNK1 or JNK2 knockout studies in mice revealed a deficiency in T-helper cells (Dong, C.; Yang, D. D.; Wysk, M.; Whitmarsh, A. J.; Davis, R. J.; Flavell, R. A., Science 1998, 282, 2092-2095; Yang, D. D.; Conze, D.; Whitmarsh, A. J.; Barrett, T.; Davis, R. J.; Rincon, M.; Flavell, R. A. Immunity 1998, 9, 575-585.; Sabapathy, K.; Hu, Y.; Kallunki, T.; Schreiber, M.; David, J. P.; Jochum, W.; Wagner, E. F.; Karin, M., Curr. Biol. 1999, 9, 116-125), whereas double knockouts are embryonic lethal (Tournier, C.; Hess, P.; Yang, D. D.; Xu, J.; Turner, T. K.; Nimnual, A.; Bar-Sagi, D.; Jones, S. N.; Flavell, R. A.; Davis, R. J., Science 2000, 288, 870-874). The JNK3 knockout mouse exhibit resistance to kainic acid induced apoptosis in the hippocampus and to subsequent seizures (Yang, D. D.; Kuan, C. Y.; Whitmarsh, A. J.; Rincon, M.; Zheng, T. S.; Davis, R. J.; Rakic, P.; Flavell, R. A., Nature 1997, 389, 865-870).
Those skilled in the art know that the JNK pathway is activated in several diseases, such as, for example, inflammatory, neurodegenerative and metabolic diseases. Those skilled in the art also know that JNK activation is required for the transformation induced by RAS, an oncogene activated in many human cancers.
In view of the interest in treating diseases mediated by c-Jun-N-terminal kinase, compounds that inhibit c-Jun-N-terminal kinase would be a welcome contribution to the art. This invention provides that contribution.
The processes involved in tumor growth, progression, and metastasis are mediated by signaling pathways that are activated in cancer cells. The ERK pathway plays a central role in regulating mammalian cell growth by relaying extracellular signals from ligand-bound cell surface tyrosine kinase receptors such as erbB family, PDGF, FGF, and VEGF receptor tyrosine kinase. Activation of the ERK pathway is via a cascade of phosphorylation events that begins with activation of Ras. Activation of Ras leads to the recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2. When activated, ERK1/2 phosphorylates several downstream targets involved in a multitude of cellular events including cytoskeletal changes and transcriptional activation. The ERK/MAPK pathway is one of the most important for cell proliferation, and it is believed that the ERK/MAPK pathway is frequently activated in many tumors. Ras genes, which are upstream of ERK1/2, are mutated in several cancers including colorectal, melanoma, breast and pancreatic tumors. The high Ras activity is accompanied by elevated ERK activity in many human tumors. In addition, mutations of BRAF, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in BRAF have been identified in melanomas (60%), thyroid cancers (greater than 40%) and colorectal cancers. These observations indicate that the ERK1/2 signalling pathway is an attractive pathway for anticancer therapies in a broad spectrum of human tumours.
Therefore, a welcome contribution to the art would be small-molecules (i.e., compounds) that inhibit ERK activity (i.e., ERK1 and ERK2 activity), which small-molecules would be useful for treating a broad spectrum of cancers, such as, for example, melanoma, pancreatic cancer, thryroid cancer, colorectal cancer, lung cancer, breast cancer, and ovarian cancer. Such a contribution is provided by this invention.